Plasma lipoproteins are soluble protein-lipid complexes that carry out lipid transport and metabolism in blood. Several major classes of lipoproteins are distinguished on the basis of their density, size, chemical compositions, and functions. Among them high-density-lipoprotein (HDL) particles alternatively denoted as high-density-lipid particles, are made up of several subclasses that vary in their average molecular weight of from 180 kDa to 360 kDa. Their average lipid and protein content is 50% by weight of each. Phosphatidylcholine (PC) accounts for 38% of the total lipid followed by cholesteryl esters and small amounts of other polar and non-polar lipids, including free cholesterol. The main protein component is apolipoprotein A-I (Apo A-I), representing about 60% of total protein weight in human HDL.
HDL particles and its major polypeptide apolipoprotein A-I participate in the reverse cholesterol transport (RCT). Therein the apolipoprotein A-I increases the efflux of cholesterol from cells, e.g. from cells of the wall of blood vessels, the binding of the lipid and the activation of the lecithin-cholesterol-acetyl-transferase and thereby the elimination of cholesterol via plasmatic flow by the liver. This is an active transport process involving the cell membrane protein ATP-binding-cassette-transporter-A-I (ABCA-I).
Apolipoprotein A-I and apolipoprotein-based therapeutics, e.g. reconstituted HDL particles, were already identified in the late 1970s and early 1980s of the last century. For apolipoprotein A-I-Milano containing lipid particles the clinical proof (meaning significant plaque reduction in arteriosclerotic patients) could be shown. Apolipoprotein A-I-Milano, a dimeric form of wild-type apolipoprotein A-I, was designed according to a naturally occurring mutant of the apolipoprotein A-I molecule. The dimer formation is enabled by the exchange of amino acid residue 173 (arginine) by cysteine allowing the formation of a disulfide bond.
In WO 2009/131704 nanostructures are reported, which are suitable for sequestering cholesterol and other molecules, comprising a core comprising an inorganic material. In WO 2006/125304 pharmaceutical compositions for treating or preventing coronary artery disease are reported. Compositions encoding apolipoproteins that are related to lipid metabolism and cardiovascular disease are reported in US 2002/0142953. In WO 2005/084642 an apoprotein-cochelate composition is reported. In WO 2009/036460 modified human apolipoprotein A-I polypeptides and their uses are reported. Plant production of dimeric and/or oligomeric forms of human apolipoprotein A-I protein muteins is reported in WO 2008/017906. In WO 2007/137400 a method and compound for the treatment of valvular stenosis is reported. In WO 2006/100567 charged lipoprotein complexes and their uses are reported.
In US 2002/0156007 apolipoprotein analogues are reported. Tetranectin trimerising polypeptides are reported in US 2010/0028995. In J. Cardiovas. Pharmacol. (51 (2008) 170-177) report Graversen, J. H., et al., that the trimerization of apolipoprotein A-I retards plasma clearance and preserves anti-atherosclerotic properties. High density lipoprotein administration—a new therapeutic modality for the treatment of cardiovascular disease is reported by Sirtori, C. R., et al. (Curr. Med. Chem. Immunol. Endocrine Metabol. Agents 5 (2005) 321-333).
In WO 03/097696 methods and compositions for the treatment of ischemic reperfusion are reported. Nanoscale bound bilayers, methods of use and production are reported in WO 2009/097587. In WO 2007/098122 methods for the treatment of macular degeneration and related eye conditions are reported. Apolipoprotein Analogues are reported in WO 02/38609. In WO 2005/041866 pharmaceutical formulations are reported. Methods and dosing regimens for the treatment and prevention of coronary syndromes are reported. Gene therapy, approaches to supply apolipoprotein A-I agonists and their use to treat dislipidemic disorders are reported in WO 99/16409. In WO 2008/106660 isolated phospholipid-protein particles are reported. Method for the prevention and treatment of diastolic dysfunction employing an apolipoprotein (APO A-I) mimetic peptide/phospholipid complex are reported in WO 2010/083611. In WO 2008/156873 APO A-I peptide mimetics are reported. Encapsulated HDL mimetic peptides are reported in WO 2008/094905. In WO 98/56906 a trimerising module is reported.